This proposal will focus on the various steps in the chain of events which characterize the inflammatory, metabolic and immunologic responses to traumatic injury. A variety of hypotheses will be tested: these studies may provide insight to potentially reverse the catabolic tissue-destructive process associated with accidental injury and thereby reduce morbidity and mortality. One project will examine the cellular and molecular mechanisms associated with insulin resistance in skeletal muscle. A second project will evaluate muscle energetics following injury, starvation and sepsis using nuclear magnetic resonance spectroscopy. Potential therapeutic measures to reverse these responses will also be studied. The mediators of the effects of endotoxin will be examined and the suppressive role of glucocorticoids on these responses will be determined. The generation of specific cytokines following endotoxin administration will be determined by characterizing the messenger RNA in circulating cells. Other modalities which are known to enhance immunologic function such as growth hormone and interleukin-2 (IL-2) combined with ibuprofen will be administered in trauma patients in controlled trials. Immunological function will be monitored, along with other endpoints such as the frequency of septic episodes. The final area of study in this Center is to determine the role of tissue oxidation in posttraumatic sepsis and organ failure. A variety of modalities will be tested, including administering parenteral or topic antioxidants to surface injury, to determine if tissue injury can be prevented and/or this tissue-destructive process reversed. All of these studies will be carried out in individual laboratories with access to a central core of facilities to enhance the effectiveness of this combined research group.